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Where next with preoperative radiation therapy for rectal cancer?
Int. J. Radiation Oncology Biol. Phys., Vol. 58, No. 2, pp. 597– 602, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/04/$–see front matter
doi:10.1016/j.ijrobp.2003.09.027
ICTR 2003
Translational Research in Clinics
WHERE NEXT WITH PREOPERATIVE RADIATION THERAPY FOR RECTAL CANCER? H. RODNEY WITHERS, M.D., D.SC.,*
AND
KARIN HAUSTERMANS, M.D., PH.D.†
*Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA; †Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven, Belgium Purpose: The basic question for radiation oncologists is what we hope to achieve from treatments that are adjuvant to surgery: better local (pelvic) control and, hopefully, because of that, fewer metastases. Chemotherapy could add to the local effect of irradiation and may also decrease distant metastases directly. Selection criteria for individual treatment could enhance the therapeutic index. Local Control: Total mesorectal excision reduces the incidence of local recurrence, but preoperative (chemo) radiation is still indicated for more advanced tumors (T3–T4) and for lymph node involvement. Pelvic recurrences arise from tumor clonogens residual beyond the surgical margins. Thus, the practice of shrinking fields to boost the dose to the primary tumor makes no sense, except for tumors that invade residual structures, such as the sacrum.Subclinical disease beyond the future surgical margins grows more quickly than the primary tumor, and hence treatment should be as intense as tolerable. A short treatment course (e.g. 5 ⴛ 5 Gy) is desirable, but this regimen, which is currently the gold standard, should be compared (as in the recently closed randomized Polish trial) with higher-dose, longer-duration chemoradiotherapy regimens. The recently closed EORTC trial 22921 examines the benefit of pre- and postoperative chemotherapy combined with a long schedule of radiation. Likewise, continuous infusion of a cycle-active agent rather than bolus administration is a logical addition to radiation therapy in the treatment of fast-growing subclinical tumor extensions. Systemic Disease: The reduction in distant metastasis rates attributable to adjuvant chemotherapy varies greatly among reports. If the reduction is of the order of 10 –25%, the efficacy of chemotherapy equates to as little as about 5 to 12.5 Gy and not more than 20 Gy of total body irradiation. Interval Between Radiation Therapy and Postradiation Surgery: Early excision after preoperative irradiation would be desirable if the primary tumor were still disseminating viable metastatic clonogens. Most tumors do not metastasize until they contain enough viable clonogens to render them clinically detectable. A dose of 10 Gy in 2 Gy fractions reduces at least 30-fold the absolute number of viable clonogens in the primary tumor, to levels that do not yield metastases from the untreated tumor. After a dose of 44 –50 Gy in 2 Gy fractions, there is little chance that the surviving tumor clonogens could regrow to a metastasis-yielding volume in any reasonable radiation–surgery interval. Thus there is no tumor-related necessity for early postradiation surgery. The importance of the interval between radiation and surgery is currently being addressed in a Swedish randomized trial. Prognostic and Predictive Characterization: Tumor volume should be included in the staging system. There are many tumor- and host-related characteristics that can be used to fingerprint the tumor to help select appropriate individual treatment. © 2004 Elsevier Inc. Rectal cancer, Surgery, (Chemo)radiation, Local control, Distant metastasis.
INTRODUCTION
staging have been introduced, the emphasis has shifted to preoperative irradiation with or without chemotherapy. The purpose of preoperative irradiation of rectal cancer is twofold:
Radiation therapy as an adjuvant treatment to surgery in the treatment of rectal cancer was commonly used in the postoperative setting. This approach allowed the use of pathologic staging to help select patients for treatment and to analyze results. Now that the utility of adjuvant radiation therapy has been established and better methods for clinical
1. To increase the probability of tumor control within the pelvis and to increase the frequency of sphincter preservation.
Reprint requests to: H. Rodney Withers, M.D., D.Sc., Department of Radiation Oncology, 200 UCLA Medical Plaza, Los Angeles, CA 90095-6951. Tel: (310) 794-1252; Fax: (310) 7949795; E-mail: [email protected]
Presented at ICTR 2003, Lugano, Switzerland, March 16 –19, 2003. Acknowledgments—J. Haas helped prepare the manuscript. Received Sep 8, 2003. Accepted for publication Sep 15, 2003. 597
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2. To stop further dissemination of metastatic clonogens pending removal of the primary tumor. The latter is rarely discussed. “Target” and dose response for increasing pelvic control Obviously, tissues removed by the surgeon go to the pathologist and cannot contribute to local recurrence. Therefore, the target for reducing pelvic recurrences is the tissues beyond the future surgical margins, mainly fibrofatty connective tissues and lymphatics and/or organs or structures to which the primary tumor is attached or which the tumor is invading. The primary tumor is only of concern if traversed by the surgical margin, as may occur when it invades structures such as the sacrum or other parts of the pelvic wall that will not be removed. Therefore, there is no point in using a shrinking field to boost the dose to the primary tumor, unless there is a high risk of an incomplete mesorectal excision (1), or the tumor is low lying, in which case sphincter preservation with adequate margins is difficult. Rather, for operable, unattached primary tumors, it is the peripheral regions of the treatment volume that should be “boosted,” and, theoretically, an “expanding” field would be more logical to raise the dose to the surgical margins and beyond. However, to actually shield the primary in an expanded field would be pointless, because there is also no advantage to be gained from reducing the dose to tissues bound for the pathologist’s tray, and it is counterproductive to risk shielding the potential surgical margins and anastomosis site. This is especially true for low-lying rectal lesions, because not only are local recurrences commoner in low-lying lesions (2, 3), but, increasingly, closer margins are being used to preserve anal function. Target and dose response for stopping dissemination of metastases For any cancer, the probability that metastases will develop increases with increase in size of the primary, but, in most cases, they do not disseminate until the primary tumor is large enough to be clinically detectable (4). For example, about 80% of patients whose rectal tumors have not metastasized to lymph nodes will be free of metastases even when the primary tumor is large enough to penetrate the full thickness of the bowel wall. In other words, it requires, on average, a mass containing of the order of 109 or 1010 malignant cells before metastatic dissemination begins to become a clinical problem. The probability of metastases from a tumor volume 10 times smaller (e.g. 108 cells) should be low (e.g. 1%) and rare from a mass 100 times smaller (107 cells). Irradiation quickly reduces the number of viable tumor clonogens available for metastasis: About 7 Gy and 14 Gy in a 2 Gy per fraction regimen reduce clonogen numbers 10-fold and 100-fold, respectively. Thus, it is reasonable to assume that a regimen of preoperative radiation therapy quickly eliminates any concern regarding the development of new micrometastases during radiation therapy or in the interval between irradiation and surgery.
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Interval between preoperative irradiation and surgical excision Although there has been a wide spectrum of approaches to the sequencing of preoperative radiotherapy and surgery for rectal cancers, the two commonest patterns have been: 1. “immediate” surgery performed within hours or days of a single dose (e.g. 5 Gy) or a short course of relatively low dose irradiation (e.g. 25 Gy in 5 fractions of 5 Gy on 5 successive days), and 2. delayed surgery, 3 to 6 weeks after a longer course of fractionated irradiation to higher doses, e.g. 40 –54 Gy in 1.8 –2.0 Gy fractions with or without chemotherapy. Facts to consider regarding the interval between preoperative irradiation and surgery are: 1. Regrowth of clonogens within the primary tumor and other tissues within the excision margins is irrelevant to the probability of local recurrence, because those clonogens will be excised. 2. Regrowth of surviving clonogens beyond the future surgical excision margins is also irrelevant, because if one or more clonogens in these tissues survives the radiation therapy, there will be a pelvic recurrence, regardless of whether it is from one residual clonogen present immediately after the last dose of radiation or from thousands of cells regrown from what was a solitary surviving cell during a several-weeks interval between irradiation and surgery. 3. Dissemination of metastases from residual primary tumor clonogens within a few weeks of a high dose (e.g. ⬎ 40 Gy) is unlikely, because of the small absolute numbers of surviving tumor clonogens (See above). For example, 40 Gy in 2 Gy fractions should reduce tumor cell survival by about six decades, e.g. from 1010 to 104 cells. Assuming irradiation does not enhance the metastatic process, this is an absolute number of cells well below the threshold for disseminating metastases. 4. Regression of the irradiated tumor may facilitate surgical removal of tumors attached to other structures: for tumors extending close to the distal surgical margin, it may facilitate surgery that preserves anal function (5–9). 5. A disadvantage of lengthening the interval is that pathology downstaging renders T and N stage less useful for selecting patients for adjuvant chemotherapy and for prognostication of outcome. From the discussion above, we conclude that the interval between preoperative radiation therapy and surgery is not critical to either local recurrence or distant metastases. (This contrasts with postoperative radiation therapy, where prolonging the overall treatment time (surgery to completion of radiation therapy) may permit growth of residual tumor clonogens, which leads to an increase in the dose necessary for their total elimination [10]).
Preoperative therapy for rectal cancer
Advantages of “immediate” surgery The advantage to immediate surgery after a short course of radiotherapy (e.g. 5 ⫻ 5 Gy) is that pathologic staging is not changed appreciably and remains a valuable guide in deciding whether to use chemotherapy (11). Also, it may be more comforting to the patient (and surgeon) to have the tumor excised as soon as possible, and the cost is less than with a long course. Compliance is not a problem with either short- or long-course preoperative irradiation, and it is better than with postoperative chemoradiation (12).
Advantages of delayed surgery The two major advantages of the “delayed” surgery approach are that higher doses of radiation are tolerated, and tumor regression is more complete at the time of surgery (13).
Fractionated dose regimens The dose used in the current standard of care for shortcourse (5-day) preoperative radiation therapy is 25 Gy in 5 Gy fractions. Assuming a range of alpha-beta ratios from 7 Gy to 12 Gy and no repopulation during the 4 days’ overall duration of treatment, the equivalent doses in 2 Gy fractions (LQED2) would range between 30 and 33 Gy. Although the short overall treatment duration in the 25 Gy in 5 fractions regimen provides a radiobiologic advantage, this is a relatively low dose that results in about a 66% reduction in the rate of local recurrence (2, 14). Higher dose regimens combined with chemotherapy could result in an even greater reduction in local recurrences and distant metastases than 25 Gy in 5 Gy fractions, but even then the decrease in pelvic recurrence rates may be less than the decreases obtained with treatment of subclinical disease in other tumor sites (15–18). It is possible that adenocarcinomas of the rectum are inherently slightly less radiosensitive than other malignancies, but that is not consistent with the observation of complete regressions after doses as low as 45 to 50 Gy in 1.8 to 2 Gy fractions (7, 9). Other causes of failure to control subclinical disease seem more likely, e.g. geographic underdosage from the use of small fields concentrated on the primary tumor, or excessive protraction of the overall treatment duration because of toxicity, holidays, or machine breakdowns. Another potential cause for a high rate of local failure is that a proportion of patients has incomplete resection (cut-through) of the primary tumor, which increases the average “subclinical” tumor burden. This reflects the expertise of the surgeon (19), and, because of difficulty with quality assurance measures, represents a major confounding variable in any analysis. Although there is some compromise of bowel function after a regimen of 5 ⫻ 5 Gy, the late effects on bowel and anal sphincter function would be predicted to be acceptable, the LQED2 Gy being about 40 Gy (assuming an alpha-beta value of 3 Gy), a total dose less than the 43 Gy calculated for 45 Gy in 1.8 Gy fractions (20).
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Effect of overall treatment duration on local control Although the time interval between preoperative radiotherapy and surgery is hypothesized to be irrelevant (within reasonable limits), the duration of the actual course of therapy is important, because the subclinical tumor deposits, which are the target of treatment, grow relatively quickly and could “escape” from control during a protracted course. A retrospective analysis of published results of preoperative radiation therapy for rectal cancer (21) showed that tumor control probability curves for local control were displaced to higher doses as the overall duration of preoperative radiation therapy was increased. The rate of increase in the dose required to maintain a constant local recurrence rate averaged as much as about 0.5 Gy per day of protraction of treatment, corresponding to a clonogen doubling time as short as 4 days. This compares with an average doubling time of 2 to 6 months for gross tumors. These relative rates of growth of large and small tumors are consistent with the concept of Gompertzian growth (22)—that is, of an exponential growth that slows exponentially with increase in tumor volume. Thus, although the growth rate of large, clinically detectable tumors may be slow, subclinical deposits may grow quickly, with little slowing of growth rate before they grow to volumes of 106 to 107 cells. An estimated doubling time as short as 4 days for these small deposits of rectal adenocarcinomas beyond the future surgical margins is consistent with similar doubling times of 3 to 4 days estimated for isolated surviving viable clonogens scattered throughout regressing squamous cell carcinomas during the latter half of a 6 to 8 weeks’ course of radiation therapy (23). Although there are pitfalls in all the estimates of growth rate for subclinical tumor deposits, it seems unlikely that the average doubling time for microscopic foci of metastatic rectal cancer would be longer than, say, 14 days and could be as short as 4 days. Such rapid growth merits fast treatment and/or increased doses and/or the addition of other cytotoxic or radiosensitizing agents. Identifying and adjusting for rapid growth and other causes of failure to control subclinical disease are more important in rectal cancer than in, for example, head-andneck cancer, because the current failure rate in rectal cancer is higher. Most reports of treatment of subclinical lymph node metastases for head-and-neck cancer show a 90% or higher rate of reduction of metastases from 50 Gy in 2 Gy fractions, whereas 25 Gy in 5 Gy fractions to the pelvis controls subclinical disease in about 66% of the (relatively low) proportion of cases that would otherwise have recurred locally. Initiation of chemotherapy If the subclinical tumor deposits that give rise to local recurrences and distant metastases grow quickly, it is logical to initiate systemic cytotoxic therapy early after diagnosis. Only the smallest of micrometastases can be eliminated by currently available chemotherapy. For radiation therapy to reduce the incidence of recurrence from subclinical disease by 20% requires between 14 and 20 Gy in 2 Gy fractions
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(17, 18), equivalent to a cytoreduction by 2 to 3 decades (i.e., to between 10⫺2 to 10⫺3). By analogy, a 20% reduction in the incidence of metastases by chemotherapy would reflect the elimination of all micrometastases containing less than 102 to 103 clonogenic cells, a situation that may exist in about 20% of the patients who harbor subclinical metastases. It requires a maximum of 10 doublings for a single clonogen to grow to a deposit greater than 103 cells (210 ⫽ 1024). Thus, if the doubling time were 4 days, the time required for a single metastatic clonogen shed at the time of diagnosis to grow beyond the reach of chemotherapy would be 10 ⫻ 4 ⫽ 40 days, or 140 days if the doubling rate were as long as 14 days. In other words, if the initiation of chemotherapy were delayed by as little as 40 days, it would lose its potential to cure anyone who harbored even only one metastatic clonogen at the time of diagnosis. If the doubling time were as long as 14 days, there would be no gain from chemotherapy if its start were delayed by 140 days or more after removal (by surgery or irradiation) of the primary source of metastases.
SUMMARY OF PRINCIPLES OF BIOLOGICALLY BASED PREOPERATIVE ADJUVANT THERAPY FOR RECTAL CANCER 1. When a T4 tumor invades or is attached to a structure that will not be removed (e.g. pelvic wall), the dose of radiation to the area of potential incomplete excision should be high. A dose of 25 Gy in 5 Gy fractions is equivalent in terms of biologic dose for tumor control to only about 32 Gy in 2 Gy fractions and has not been recommended for this stage of tumor (Note that there were few T4 tumors treated in the randomized trials of preoperative radiation therapy that showed an overall advantage from this dose). 2. For stages less than T4, preoperative chemoradiotherapy eliminates the need for early surgical removal of the primary tumor. New metastatic spread is eliminated, regrowth of residual clonogens in the primary tumor does not impair the effectiveness of surgery, and a bad outcome is unchanged by regrowth if clonogens survive outside the future surgical margins. 3. Preoperative chemotherapy and radiation therapy should be initiated promptly and intensively to counteract the effect on curability from a fast growth rate of small subclinical tumor deposits in the pelvis or distant organs (21). It is probably of little use to extend adjuvant chemotherapy over several months or to administer it postoperatively after aggressive systemic preoperative therapy. 4. Radiation therapy boost doses using shrinking fields are useful for T4 tumors, but for lower stages, reduced portal size for boosting is not logical.
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FUTURE DIRECTIONS Staging In sites other than rectum, the volume of the tumor mass has been shown to be a useful predictor of radiation response (24). Although the TNM staging is useful and has a simpler nomenclature than the various modifications of the Dukes staging system, its prognostic value might be improved if the volume of the tumor were determined and added to the staging. Tumor volume is a prognostic indicator superior to tumor stage, which only partially reflects tumor size and for rectal cancer is mainly correlated to wall penetration and operability. Tumors of even identical stage may vary by factors of more than 100 in volume. The circumferential resection margin has also been shown to be an important prognostic factor and should be assessed using MRI (1, 25) and included in prognostications and decisions regarding (neo)adjuvant radiotherapy. Biologic “fingerprinting” As is the case for all cancers, significant improvements in tumor control and reduced toxicities could be achieved if traditional factors such as staging, histology, and immunochemistry could be supplemented by genetic and functional characteristics and microenvironmental parameters of the tumors to predict accurately their responses to treatment (26 –28). Biologic fingerprinting can help predict radiation and chemotherapy responses, as well as responses to various biologic molecules. Numerous molecular characteristics of cells can be quickly displayed using cDNA microarray technology, and significant improvements in therapeutic design may be achieved with improved statistical analysis of microarray gene expression patterns (29, 30). Recently, molecular characteristics of patients’ tumors were found to explain a large difference between men and women in the responses of colorectal cancers to fluoropyrimidine chemotherapy, as well as between proximal and distal colon cancers (31). Reflecting this, men with carcinoma of the rectum probably gain little survival advantage from adjuvant treatment with fluoropyrimidines (31). Surgery The advent of total mesorectal excision surgery has greatly altered the probability of recurrence in the pelvis. If the money spent on developing one chemotherapeutic agent were spent on training surgeons in total mesorectal excision and on assuring technical expertise, the return would far exceed that of any chemotherapy agent yet tested in colorectal cancer. It would also lower the usage of radiation therapy and thereby further increase cost-effectiveness. Neoadjuvant therapy Total mesorectal excision is now the gold standard for surgery for carcinoma of the rectum (32). It was still associated with a significant incidence of local recurrence in the small number of patients with advanced lesions included in the trial, the actuarial incidence at 5 years approaching 20%
Preoperative therapy for rectal cancer
for T2–T3, N0–N1 tumors. The incidence of distant metastases in this subset of patients was between 30% and 40%, about twice the rate of pelvic recurrences. Therefore, in this group of patients receiving the gold standard of surgical excision, there is still a need for aggressive local and systemic therapy. Various combinations of cytotoxic drugs and biologically active molecules against tumor cells or vasculature should be used in clinical trials. It would also seem worthwhile devoting more effort to optimizing the kinetics of drug administration. For example, it has been shown that continuous infusion of 5-fluorouracil (5-FU) combined with radiation is superior to bolus 5-FU (33, 34). In the metastasized setting, prolonged 5-FU infusion has also been shown to be superior to the bolus regimens in terms of response rates, time to progression, and toxicity (35, 36). Oral 5-FU prodrugs can mimic prolonged venous infusion and offer a potentially enhanced therapeutic ratio (37). In the mid 1990s, several new cytotoxic drugs became available. Phase III studies with irinotecan and oxaliplatin have shown that combination treatment is more active than 5-FU/leukovorin alone (38 – 41). The addition of oxaliplatin to preoperative chemoradiation has shown promising results in a Phase II study (42), but toxicity due to the radiation renders it very difficult to administer more intense
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chemotherapy during the radiation. However, the toxicity of radiation can be reduced, and hence the intensity of chemotherapy increased, by employing modern imaging techniques (including PET [43]) to identify primary disease and nodal metastases and so target better those volumes harboring tumor utilizing technical advances such as intensity modulated radiotherapy or intensity modulated arc therapy. For example, a schedule of 45 Gy in 1.8 Gy fractions may be delivered to an area at risk for bearing subclinical disease, whereas an area of increased PET activity (e.g. in sacral hollow) could concurrently receive 55 Gy in 2.2 Gy fractions. Doses to critical normal tissues could also be lowered using these techniques. By this selective delivery of dose to the tumor using functional imaging techniques, the normal tissues are able to tolerate the higher doses of chemotherapy necessary to improve the treatment of subclinical distant metastases. The increase in capacity to escalate chemotherapy is one of the major challenges in preoperative chemoirradiation. Most of the above-mentioned issues are now the subject of ongoing or recently completed randomized trials, and we have to await the results before we can test our hypotheses and speculate further on the future in the treatment of rectal cancer.
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doi:10.1016/j.ijrobp.2003.09.027
ICTR 2003
Translational Research in Clinics
WHERE NEXT WITH PREOPERATIVE RADIATION THERAPY FOR RECTAL CANCER? H. RODNEY WITHERS, M.D., D.SC.,*
AND
KARIN HAUSTERMANS, M.D., PH.D.†
*Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA; †Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven, Belgium Purpose: The basic question for radiation oncologists is what we hope to achieve from treatments that are adjuvant to surgery: better local (pelvic) control and, hopefully, because of that, fewer metastases. Chemotherapy could add to the local effect of irradiation and may also decrease distant metastases directly. Selection criteria for individual treatment could enhance the therapeutic index. Local Control: Total mesorectal excision reduces the incidence of local recurrence, but preoperative (chemo) radiation is still indicated for more advanced tumors (T3–T4) and for lymph node involvement. Pelvic recurrences arise from tumor clonogens residual beyond the surgical margins. Thus, the practice of shrinking fields to boost the dose to the primary tumor makes no sense, except for tumors that invade residual structures, such as the sacrum.Subclinical disease beyond the future surgical margins grows more quickly than the primary tumor, and hence treatment should be as intense as tolerable. A short treatment course (e.g. 5 ⴛ 5 Gy) is desirable, but this regimen, which is currently the gold standard, should be compared (as in the recently closed randomized Polish trial) with higher-dose, longer-duration chemoradiotherapy regimens. The recently closed EORTC trial 22921 examines the benefit of pre- and postoperative chemotherapy combined with a long schedule of radiation. Likewise, continuous infusion of a cycle-active agent rather than bolus administration is a logical addition to radiation therapy in the treatment of fast-growing subclinical tumor extensions. Systemic Disease: The reduction in distant metastasis rates attributable to adjuvant chemotherapy varies greatly among reports. If the reduction is of the order of 10 –25%, the efficacy of chemotherapy equates to as little as about 5 to 12.5 Gy and not more than 20 Gy of total body irradiation. Interval Between Radiation Therapy and Postradiation Surgery: Early excision after preoperative irradiation would be desirable if the primary tumor were still disseminating viable metastatic clonogens. Most tumors do not metastasize until they contain enough viable clonogens to render them clinically detectable. A dose of 10 Gy in 2 Gy fractions reduces at least 30-fold the absolute number of viable clonogens in the primary tumor, to levels that do not yield metastases from the untreated tumor. After a dose of 44 –50 Gy in 2 Gy fractions, there is little chance that the surviving tumor clonogens could regrow to a metastasis-yielding volume in any reasonable radiation–surgery interval. Thus there is no tumor-related necessity for early postradiation surgery. The importance of the interval between radiation and surgery is currently being addressed in a Swedish randomized trial. Prognostic and Predictive Characterization: Tumor volume should be included in the staging system. There are many tumor- and host-related characteristics that can be used to fingerprint the tumor to help select appropriate individual treatment. © 2004 Elsevier Inc. Rectal cancer, Surgery, (Chemo)radiation, Local control, Distant metastasis.
INTRODUCTION
staging have been introduced, the emphasis has shifted to preoperative irradiation with or without chemotherapy. The purpose of preoperative irradiation of rectal cancer is twofold:
Radiation therapy as an adjuvant treatment to surgery in the treatment of rectal cancer was commonly used in the postoperative setting. This approach allowed the use of pathologic staging to help select patients for treatment and to analyze results. Now that the utility of adjuvant radiation therapy has been established and better methods for clinical
1. To increase the probability of tumor control within the pelvis and to increase the frequency of sphincter preservation.
Reprint requests to: H. Rodney Withers, M.D., D.Sc., Department of Radiation Oncology, 200 UCLA Medical Plaza, Los Angeles, CA 90095-6951. Tel: (310) 794-1252; Fax: (310) 7949795; E-mail: [email protected]
Presented at ICTR 2003, Lugano, Switzerland, March 16 –19, 2003. Acknowledgments—J. Haas helped prepare the manuscript. Received Sep 8, 2003. Accepted for publication Sep 15, 2003. 597
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2. To stop further dissemination of metastatic clonogens pending removal of the primary tumor. The latter is rarely discussed. “Target” and dose response for increasing pelvic control Obviously, tissues removed by the surgeon go to the pathologist and cannot contribute to local recurrence. Therefore, the target for reducing pelvic recurrences is the tissues beyond the future surgical margins, mainly fibrofatty connective tissues and lymphatics and/or organs or structures to which the primary tumor is attached or which the tumor is invading. The primary tumor is only of concern if traversed by the surgical margin, as may occur when it invades structures such as the sacrum or other parts of the pelvic wall that will not be removed. Therefore, there is no point in using a shrinking field to boost the dose to the primary tumor, unless there is a high risk of an incomplete mesorectal excision (1), or the tumor is low lying, in which case sphincter preservation with adequate margins is difficult. Rather, for operable, unattached primary tumors, it is the peripheral regions of the treatment volume that should be “boosted,” and, theoretically, an “expanding” field would be more logical to raise the dose to the surgical margins and beyond. However, to actually shield the primary in an expanded field would be pointless, because there is also no advantage to be gained from reducing the dose to tissues bound for the pathologist’s tray, and it is counterproductive to risk shielding the potential surgical margins and anastomosis site. This is especially true for low-lying rectal lesions, because not only are local recurrences commoner in low-lying lesions (2, 3), but, increasingly, closer margins are being used to preserve anal function. Target and dose response for stopping dissemination of metastases For any cancer, the probability that metastases will develop increases with increase in size of the primary, but, in most cases, they do not disseminate until the primary tumor is large enough to be clinically detectable (4). For example, about 80% of patients whose rectal tumors have not metastasized to lymph nodes will be free of metastases even when the primary tumor is large enough to penetrate the full thickness of the bowel wall. In other words, it requires, on average, a mass containing of the order of 109 or 1010 malignant cells before metastatic dissemination begins to become a clinical problem. The probability of metastases from a tumor volume 10 times smaller (e.g. 108 cells) should be low (e.g. 1%) and rare from a mass 100 times smaller (107 cells). Irradiation quickly reduces the number of viable tumor clonogens available for metastasis: About 7 Gy and 14 Gy in a 2 Gy per fraction regimen reduce clonogen numbers 10-fold and 100-fold, respectively. Thus, it is reasonable to assume that a regimen of preoperative radiation therapy quickly eliminates any concern regarding the development of new micrometastases during radiation therapy or in the interval between irradiation and surgery.
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Interval between preoperative irradiation and surgical excision Although there has been a wide spectrum of approaches to the sequencing of preoperative radiotherapy and surgery for rectal cancers, the two commonest patterns have been: 1. “immediate” surgery performed within hours or days of a single dose (e.g. 5 Gy) or a short course of relatively low dose irradiation (e.g. 25 Gy in 5 fractions of 5 Gy on 5 successive days), and 2. delayed surgery, 3 to 6 weeks after a longer course of fractionated irradiation to higher doses, e.g. 40 –54 Gy in 1.8 –2.0 Gy fractions with or without chemotherapy. Facts to consider regarding the interval between preoperative irradiation and surgery are: 1. Regrowth of clonogens within the primary tumor and other tissues within the excision margins is irrelevant to the probability of local recurrence, because those clonogens will be excised. 2. Regrowth of surviving clonogens beyond the future surgical excision margins is also irrelevant, because if one or more clonogens in these tissues survives the radiation therapy, there will be a pelvic recurrence, regardless of whether it is from one residual clonogen present immediately after the last dose of radiation or from thousands of cells regrown from what was a solitary surviving cell during a several-weeks interval between irradiation and surgery. 3. Dissemination of metastases from residual primary tumor clonogens within a few weeks of a high dose (e.g. ⬎ 40 Gy) is unlikely, because of the small absolute numbers of surviving tumor clonogens (See above). For example, 40 Gy in 2 Gy fractions should reduce tumor cell survival by about six decades, e.g. from 1010 to 104 cells. Assuming irradiation does not enhance the metastatic process, this is an absolute number of cells well below the threshold for disseminating metastases. 4. Regression of the irradiated tumor may facilitate surgical removal of tumors attached to other structures: for tumors extending close to the distal surgical margin, it may facilitate surgery that preserves anal function (5–9). 5. A disadvantage of lengthening the interval is that pathology downstaging renders T and N stage less useful for selecting patients for adjuvant chemotherapy and for prognostication of outcome. From the discussion above, we conclude that the interval between preoperative radiation therapy and surgery is not critical to either local recurrence or distant metastases. (This contrasts with postoperative radiation therapy, where prolonging the overall treatment time (surgery to completion of radiation therapy) may permit growth of residual tumor clonogens, which leads to an increase in the dose necessary for their total elimination [10]).
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Advantages of “immediate” surgery The advantage to immediate surgery after a short course of radiotherapy (e.g. 5 ⫻ 5 Gy) is that pathologic staging is not changed appreciably and remains a valuable guide in deciding whether to use chemotherapy (11). Also, it may be more comforting to the patient (and surgeon) to have the tumor excised as soon as possible, and the cost is less than with a long course. Compliance is not a problem with either short- or long-course preoperative irradiation, and it is better than with postoperative chemoradiation (12).
Advantages of delayed surgery The two major advantages of the “delayed” surgery approach are that higher doses of radiation are tolerated, and tumor regression is more complete at the time of surgery (13).
Fractionated dose regimens The dose used in the current standard of care for shortcourse (5-day) preoperative radiation therapy is 25 Gy in 5 Gy fractions. Assuming a range of alpha-beta ratios from 7 Gy to 12 Gy and no repopulation during the 4 days’ overall duration of treatment, the equivalent doses in 2 Gy fractions (LQED2) would range between 30 and 33 Gy. Although the short overall treatment duration in the 25 Gy in 5 fractions regimen provides a radiobiologic advantage, this is a relatively low dose that results in about a 66% reduction in the rate of local recurrence (2, 14). Higher dose regimens combined with chemotherapy could result in an even greater reduction in local recurrences and distant metastases than 25 Gy in 5 Gy fractions, but even then the decrease in pelvic recurrence rates may be less than the decreases obtained with treatment of subclinical disease in other tumor sites (15–18). It is possible that adenocarcinomas of the rectum are inherently slightly less radiosensitive than other malignancies, but that is not consistent with the observation of complete regressions after doses as low as 45 to 50 Gy in 1.8 to 2 Gy fractions (7, 9). Other causes of failure to control subclinical disease seem more likely, e.g. geographic underdosage from the use of small fields concentrated on the primary tumor, or excessive protraction of the overall treatment duration because of toxicity, holidays, or machine breakdowns. Another potential cause for a high rate of local failure is that a proportion of patients has incomplete resection (cut-through) of the primary tumor, which increases the average “subclinical” tumor burden. This reflects the expertise of the surgeon (19), and, because of difficulty with quality assurance measures, represents a major confounding variable in any analysis. Although there is some compromise of bowel function after a regimen of 5 ⫻ 5 Gy, the late effects on bowel and anal sphincter function would be predicted to be acceptable, the LQED2 Gy being about 40 Gy (assuming an alpha-beta value of 3 Gy), a total dose less than the 43 Gy calculated for 45 Gy in 1.8 Gy fractions (20).
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Effect of overall treatment duration on local control Although the time interval between preoperative radiotherapy and surgery is hypothesized to be irrelevant (within reasonable limits), the duration of the actual course of therapy is important, because the subclinical tumor deposits, which are the target of treatment, grow relatively quickly and could “escape” from control during a protracted course. A retrospective analysis of published results of preoperative radiation therapy for rectal cancer (21) showed that tumor control probability curves for local control were displaced to higher doses as the overall duration of preoperative radiation therapy was increased. The rate of increase in the dose required to maintain a constant local recurrence rate averaged as much as about 0.5 Gy per day of protraction of treatment, corresponding to a clonogen doubling time as short as 4 days. This compares with an average doubling time of 2 to 6 months for gross tumors. These relative rates of growth of large and small tumors are consistent with the concept of Gompertzian growth (22)—that is, of an exponential growth that slows exponentially with increase in tumor volume. Thus, although the growth rate of large, clinically detectable tumors may be slow, subclinical deposits may grow quickly, with little slowing of growth rate before they grow to volumes of 106 to 107 cells. An estimated doubling time as short as 4 days for these small deposits of rectal adenocarcinomas beyond the future surgical margins is consistent with similar doubling times of 3 to 4 days estimated for isolated surviving viable clonogens scattered throughout regressing squamous cell carcinomas during the latter half of a 6 to 8 weeks’ course of radiation therapy (23). Although there are pitfalls in all the estimates of growth rate for subclinical tumor deposits, it seems unlikely that the average doubling time for microscopic foci of metastatic rectal cancer would be longer than, say, 14 days and could be as short as 4 days. Such rapid growth merits fast treatment and/or increased doses and/or the addition of other cytotoxic or radiosensitizing agents. Identifying and adjusting for rapid growth and other causes of failure to control subclinical disease are more important in rectal cancer than in, for example, head-andneck cancer, because the current failure rate in rectal cancer is higher. Most reports of treatment of subclinical lymph node metastases for head-and-neck cancer show a 90% or higher rate of reduction of metastases from 50 Gy in 2 Gy fractions, whereas 25 Gy in 5 Gy fractions to the pelvis controls subclinical disease in about 66% of the (relatively low) proportion of cases that would otherwise have recurred locally. Initiation of chemotherapy If the subclinical tumor deposits that give rise to local recurrences and distant metastases grow quickly, it is logical to initiate systemic cytotoxic therapy early after diagnosis. Only the smallest of micrometastases can be eliminated by currently available chemotherapy. For radiation therapy to reduce the incidence of recurrence from subclinical disease by 20% requires between 14 and 20 Gy in 2 Gy fractions
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(17, 18), equivalent to a cytoreduction by 2 to 3 decades (i.e., to between 10⫺2 to 10⫺3). By analogy, a 20% reduction in the incidence of metastases by chemotherapy would reflect the elimination of all micrometastases containing less than 102 to 103 clonogenic cells, a situation that may exist in about 20% of the patients who harbor subclinical metastases. It requires a maximum of 10 doublings for a single clonogen to grow to a deposit greater than 103 cells (210 ⫽ 1024). Thus, if the doubling time were 4 days, the time required for a single metastatic clonogen shed at the time of diagnosis to grow beyond the reach of chemotherapy would be 10 ⫻ 4 ⫽ 40 days, or 140 days if the doubling rate were as long as 14 days. In other words, if the initiation of chemotherapy were delayed by as little as 40 days, it would lose its potential to cure anyone who harbored even only one metastatic clonogen at the time of diagnosis. If the doubling time were as long as 14 days, there would be no gain from chemotherapy if its start were delayed by 140 days or more after removal (by surgery or irradiation) of the primary source of metastases.
SUMMARY OF PRINCIPLES OF BIOLOGICALLY BASED PREOPERATIVE ADJUVANT THERAPY FOR RECTAL CANCER 1. When a T4 tumor invades or is attached to a structure that will not be removed (e.g. pelvic wall), the dose of radiation to the area of potential incomplete excision should be high. A dose of 25 Gy in 5 Gy fractions is equivalent in terms of biologic dose for tumor control to only about 32 Gy in 2 Gy fractions and has not been recommended for this stage of tumor (Note that there were few T4 tumors treated in the randomized trials of preoperative radiation therapy that showed an overall advantage from this dose). 2. For stages less than T4, preoperative chemoradiotherapy eliminates the need for early surgical removal of the primary tumor. New metastatic spread is eliminated, regrowth of residual clonogens in the primary tumor does not impair the effectiveness of surgery, and a bad outcome is unchanged by regrowth if clonogens survive outside the future surgical margins. 3. Preoperative chemotherapy and radiation therapy should be initiated promptly and intensively to counteract the effect on curability from a fast growth rate of small subclinical tumor deposits in the pelvis or distant organs (21). It is probably of little use to extend adjuvant chemotherapy over several months or to administer it postoperatively after aggressive systemic preoperative therapy. 4. Radiation therapy boost doses using shrinking fields are useful for T4 tumors, but for lower stages, reduced portal size for boosting is not logical.
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FUTURE DIRECTIONS Staging In sites other than rectum, the volume of the tumor mass has been shown to be a useful predictor of radiation response (24). Although the TNM staging is useful and has a simpler nomenclature than the various modifications of the Dukes staging system, its prognostic value might be improved if the volume of the tumor were determined and added to the staging. Tumor volume is a prognostic indicator superior to tumor stage, which only partially reflects tumor size and for rectal cancer is mainly correlated to wall penetration and operability. Tumors of even identical stage may vary by factors of more than 100 in volume. The circumferential resection margin has also been shown to be an important prognostic factor and should be assessed using MRI (1, 25) and included in prognostications and decisions regarding (neo)adjuvant radiotherapy. Biologic “fingerprinting” As is the case for all cancers, significant improvements in tumor control and reduced toxicities could be achieved if traditional factors such as staging, histology, and immunochemistry could be supplemented by genetic and functional characteristics and microenvironmental parameters of the tumors to predict accurately their responses to treatment (26 –28). Biologic fingerprinting can help predict radiation and chemotherapy responses, as well as responses to various biologic molecules. Numerous molecular characteristics of cells can be quickly displayed using cDNA microarray technology, and significant improvements in therapeutic design may be achieved with improved statistical analysis of microarray gene expression patterns (29, 30). Recently, molecular characteristics of patients’ tumors were found to explain a large difference between men and women in the responses of colorectal cancers to fluoropyrimidine chemotherapy, as well as between proximal and distal colon cancers (31). Reflecting this, men with carcinoma of the rectum probably gain little survival advantage from adjuvant treatment with fluoropyrimidines (31). Surgery The advent of total mesorectal excision surgery has greatly altered the probability of recurrence in the pelvis. If the money spent on developing one chemotherapeutic agent were spent on training surgeons in total mesorectal excision and on assuring technical expertise, the return would far exceed that of any chemotherapy agent yet tested in colorectal cancer. It would also lower the usage of radiation therapy and thereby further increase cost-effectiveness. Neoadjuvant therapy Total mesorectal excision is now the gold standard for surgery for carcinoma of the rectum (32). It was still associated with a significant incidence of local recurrence in the small number of patients with advanced lesions included in the trial, the actuarial incidence at 5 years approaching 20%
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for T2–T3, N0–N1 tumors. The incidence of distant metastases in this subset of patients was between 30% and 40%, about twice the rate of pelvic recurrences. Therefore, in this group of patients receiving the gold standard of surgical excision, there is still a need for aggressive local and systemic therapy. Various combinations of cytotoxic drugs and biologically active molecules against tumor cells or vasculature should be used in clinical trials. It would also seem worthwhile devoting more effort to optimizing the kinetics of drug administration. For example, it has been shown that continuous infusion of 5-fluorouracil (5-FU) combined with radiation is superior to bolus 5-FU (33, 34). In the metastasized setting, prolonged 5-FU infusion has also been shown to be superior to the bolus regimens in terms of response rates, time to progression, and toxicity (35, 36). Oral 5-FU prodrugs can mimic prolonged venous infusion and offer a potentially enhanced therapeutic ratio (37). In the mid 1990s, several new cytotoxic drugs became available. Phase III studies with irinotecan and oxaliplatin have shown that combination treatment is more active than 5-FU/leukovorin alone (38 – 41). The addition of oxaliplatin to preoperative chemoradiation has shown promising results in a Phase II study (42), but toxicity due to the radiation renders it very difficult to administer more intense
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chemotherapy during the radiation. However, the toxicity of radiation can be reduced, and hence the intensity of chemotherapy increased, by employing modern imaging techniques (including PET [43]) to identify primary disease and nodal metastases and so target better those volumes harboring tumor utilizing technical advances such as intensity modulated radiotherapy or intensity modulated arc therapy. For example, a schedule of 45 Gy in 1.8 Gy fractions may be delivered to an area at risk for bearing subclinical disease, whereas an area of increased PET activity (e.g. in sacral hollow) could concurrently receive 55 Gy in 2.2 Gy fractions. Doses to critical normal tissues could also be lowered using these techniques. By this selective delivery of dose to the tumor using functional imaging techniques, the normal tissues are able to tolerate the higher doses of chemotherapy necessary to improve the treatment of subclinical distant metastases. The increase in capacity to escalate chemotherapy is one of the major challenges in preoperative chemoirradiation. Most of the above-mentioned issues are now the subject of ongoing or recently completed randomized trials, and we have to await the results before we can test our hypotheses and speculate further on the future in the treatment of rectal cancer.
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